tbuckley/cabot-search huggingface dataset:
Clonal structure, stability and dynamics of human memory B cells and circulating plasmablasts
Authors: Ganesh E. Phad, Dora Pinto, Mathilde Foglierini, Murodzhon Akhmedov, Riccardo L. Rossi, Emilia Malvicini, Antonino Cassotta, Chiara Silacci Fregni, Ludovica Bruno, Federica Sallusto, Antonio Lanzavecchia
Journal: Nature Immunology (2022)

Abstract Memory B cells persist for a lifetime and rapidly differentiate into antibody-producing plasmablasts and plasma cells upon antigen re-encounter. The clonal relationship and evolution of memory B cells and circulating plasmablasts is not well understood. Using single-cell sequencing combined with isolation of specific antibodies, we found that in two healthy donors, the memory B cell repertoire was dominated by large IgM, IgA and IgG2 clonal families, whereas IgG1 families, including those specific for recall antigens, were of small size. Analysis of multiyear samples demonstrated stability of memory B cell clonal families and revealed that a large fraction of recently generated plasmablasts was derived from long-term memory B cell families and was found recurrently. Collectively, this study provides a systematic description of the structure, stability and dynamics of the human memory B cell pool and suggests that memory B cells may be active at any time point in the generation of plasmablasts.
AB0044 REDUCED PERIPHERAL BLOOD MYELOID CELLS IN PATIENTS WITH VEXAS SYNDROME
Authors: V. Jachiet, L. Ricard, P. Hirsch, F. Malard, L.P. Zhao, L. Adès, P. Fenaux, O. Fain, M. Mohty, B. Gaugler, A. Mekinian
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> Systemic inflammatory or dysimmune diseases (SIDDs) are encountered in up to a quarter of patients with myelodysplastic syndromes (MDS). Recently identified VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, associated with somatic mutations in UBA1, encompasses a range of severe inflammatory conditions along with hematologic abnormalities, including myelodysplasia. Only limited data are available on the pathophysiology of MDS-associated SIDDs, and especially about the role of different myeloid cell subsets. <h3>Objectives</h3> The aim of this study was to describe the phenotype of myeloid immune cells (dendritic cells and monocytes) in MDS patients with associated SIDDs, and to compare their distribution with MDS patients without SIDDs and controls. <h3>Methods</h3> Phenotype analysis by flow cytometry from PBMCs of 14 MDS patients with SIDDs, 23 MDS patients without SIDDs and 7 controls without MDS and SIDDs. Eight of the 14 MDS/SIDDs patients (57%) had a somatic <i>UBA1</i> mutation. <h3>Results</h3> In this study analyzing peripheral blood myeloid immune cells in MDS patients with and without SIDDs, we observed a quantitative reduction of different DC and monocyte subsets in MDS/SIDDs patients, especially in patients with active SIDDs and above all in patients with newly described VEXAS syndrome. <h3>Conclusion</h3> Further functional studies are warranted to better understand the mechanisms and the consequences of the phenotypic modulations of immune myeloid cells in the pathophysiology of MDS-associated SIDDs, especially in VEXAS syndrome. <h3>Disclosure of Interests</h3> None declared
Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel–Lindau syndrome
Authors: Shuijie Li, Wenyu Li, Juan Yuan, Petra Bullova, Jieyu Wu, Xuepei Zhang, Yong Liu, Monika Plescher, Javier Rodriguez, Oscar C. Bedoya-Reina, Paulo R. Jannig, Paula Valente-Silva, Meng Yu, Marie Arsenian Henriksson, Roman A. Zubarev, Anna Smed-Sörensen, Carolyn K. Suzuki, Jorge L. Ruas, Johan Holmberg, Catharina Larsson, C. Christofer Juhlin, Alex von Kriegsheim, Yihai Cao, Susanne Schlisio
Journal: Nature Metabolism (2022)

Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumours arising in the von Hippel-Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the von Hippel-Lindau tumour-suppressor protein, which stabilizes TFAM by preventing mitochondrial proteolysis. Cells lacking wild-type VHL or in which EGLN3 is inactivated have reduced mitochondrial mass. Tumorigenic VHL variants leading to different clinical manifestations fail to bind hydroxylated TFAM. In contrast, cells harbouring the Chuvash polycythaemia VHLR200W mutation, involved in hypoxia-sensing disorders without tumour development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumours, such as pheochromocytoma and renal cell carcinoma cells, display low mitochondrial content, suggesting that impaired mitochondrial biogenesis is linked to VHL tumorigenesis. Finally, inhibiting proteolysis by targeting LONP1 increases mitochondrial content in VHL-deficient cells and sensitizes therapy-resistant tumours to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumours by focusing on the mitochondria.
Results of a National Survey of Program Directors’ Perspectives on a Pass/Fail US Medical Licensing Examination Step 1
Authors: Om U. Patel, William K. Haynes, Kaitlin G. Burge, Ishant S. Yadav, Todd Peterson, Andres Camino, Nicholas J. Van Wagoner
Journal: JAMA Network Open (2022)

This survey study of medical residency program directors assesses differences in the relative importance of the US Medical Licensing Examination (USMLE) Step 1 in resident selection following its transition to pass/fail evaluation.
AB0203 25-HYDROXYVITAMIN D [25 (OH) D] LEVEL IN POSTMENOPAUSAL WOMEN WITH RHEUMATOID ARTHRITIS, ITS RELATIONSHIP WITH THE COURSE OF THE DISEASE, VDR (FokI) GENE POLYMORPHISM AND BONE MINERAL DENSITY.
Authors: Y. Seheda, S. Shevchuk, O. Galiutina, I. Kuvikova, O. Shevchuk
Journal: Annals of the Rheumatic Diseases (2022)

Background Osteoporosis is known to be a common concomitant state in postmenopausal women with rheumatoid arthritis, but its development cannot be explained only by increasing of age, hormonal disorders, disease duration and glucocorticosteroid intake. Vitamin D deficiency may be one of the major risk factors, but its prevalence in the Ukrainian cohort of postmenopausal RA patients is unknown, and the factors on which it depends have not been established. Objectives To analyze the level of 25-hydroxyvitamin D [25 (OH) D] in postmenopausal women with rheumatoid arthritis (RA) and to investigate its relationship with the course of the disease, VDR (FokI) gene polymorphism and bone mineral density (BMD). Methods The study included 81 postmenopausal RA patients and 21 postmenopausal age-matched women without RA as a control group. All patients were screened for demographic, disease course and treatment data. Serum 25-hydroxyvitamin D [25 (OH) D] level and VDR (FokI) gene polymorphism were measured by enzyme-linked immunosorbent assay (ELISA). Levels of 25-hydroxyvitamin D [25 (OH) D] 20-30 ng / ml were defined as insuficiency and less than 20 ng/ml as deficiency. BMD was measured in the lumbar spine and proximal femur using double X-ray absorptiometry. Osteoporosis was diagnosed in case of BMD&gt; -2.5 T. Results The analysis has showed that serum vitamin D level in RA group was significantly lower than in control group (11.54 ng/ml vs. 15.25 ng/ml; p &lt;0.01). In addition, the incidence of vitamin D insuficiency and deficiency was higher in RA patients than in control group. In particular, abnormal vitamin D level was diagnosed in 74.1% of RA patients, among whom 25 (30,9%) patients had vitamin D insuficiency and 35 (43.2%) patients had vitamin D deficiency. In control group 8 (38.1%) persons had vitamin D insuficiency, and 6 (28.6%) persons had vitamin D deficiency. There was an inverse correlation between vitamin D levels and RA activity assessed by DAS28 (p &lt;0.001), CDAI (p = 0.001), ESR and CRP (p &lt;0.001) but not with age, daily glucocorticosteroid dose and disease duration. In addition, significant correlation was revieled between VDR (FokI) gene polymorphism and vitamin D deficiency, as well as low BMD in postmenopausal women with rheumatoid arthritis (p &lt;0.001) Conclusion Low 25-hydroxyvitamin D [25 (OH) D] level and VDR (FokI) gene polymorphism are independent risk factors of osteoporosis in postmenopausal women with RA. Vitamin D deficiency is associated with RA activity and not depends on age, glucocorticosteroid daily dose and disease duration. Disclosure of Interests None declared
AB0162 PREDICTION OF TREATMENT DISCONTINUATION DUE TO ADVERSE EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS USED BIOLOGICAL DMARDs AND TARGETED SYNTHETIC DMARDs
Authors: E. Koltsova, G. Lukina, E. Shmidt, K. Lytkina, E. Zhilyaev
Journal: Annals of the Rheumatic Diseases (2022)

Background The main goal of rheumatoid arthritis (RA) patients therapy is to achieve low activity or remission of the disease (T2T strategy). However, it is sometimes necessary to interrupt effective treatment due to the development of adverse events. Objectives To reveal predictors of target drug withdrawal due to adverse RA. Methods The study includes patients with RA used bDMARDs, total 1217 treatment events. Search for predictors was carried out in two steps. At the first step were selected variables which demonstrated significant correlation with time to treatment discontinuation in Kaplan-Meier analysis. At the second step selected factors were included in the Cox regression model. The final set of independent significant predictors was obtained by backward stepwise variable selection. Results Of 661 patients 85,8% were women, the mean age of onset disease 58,7 ± 12,9 years, the mean disease duration 14,6 years. The longest mean time till withdrawal due to adverse events had Abatacept, Toficitinib, Tocilizumab, the shortest time had Infliximab. There were 146 cases of therapy discontinuation due to adverse events. The side effects that caused the cancellation of treatment were: infections of respiratory system, skin, urinary system, allergic and infusion reactions, drug-induced hepatitis, changes in the hematopoietic system, death and other. Рresence of rheumatoid nodules (p &lt; 0.001), higher doses of glucocorticoids (p&lt;0.001), lower doses of methotrexate (p = 0.009) were independent significant predictors of increased risk of bDMARDs withdrawal due to adverse events. Used target drug also showed independent significant correlation with this risk. Relative risk (compared to Etanercept) was for Infliximab - 6.57 (CI: 3.69-11.73), Certolizumab pegol - 2.61 (CI: 1.23-5.56), Abatacept - 1.23 (CI: 0.65-2.30), Adalimumab - 1.37 (CI: 0.75-2.50), Rituximab - 0.56 (CI: 0.26-1.20), Tofacitinib - 0.46 (CI: 0.15-1.40), Tocilizumab - 0.77 (CI: 0.37-1.60). Conclusion Growth glucocorticoid doses for every 1 mg increases the risk of discontinuation of therapy by 8.7%. Reducing the methotrexate doses for every 1 mg increases the risk of discontinuation of bDMARDs and tsDMARDS by 3%. There are significant differences between target drugs for the risk of cancellation due to adverse events. High risk of infliximab discontinuation was associated more with infusion reactions and infection, discontinuation of certolizumab pegol was associated with infection. References [1]The identified predictors for the treatment withdrawal due to side effects may be discussed to identify measures necessary to prevent adverse events in patients with RA who are using bDMARDs and tsDMARDs. These measures are: the use of full doses of methotrexate, avoid long-term use of glucocorticoids, or prescription of the targeted drug with lower risk of adverse events. Disclosure of Interests None declared
POS0401 SERUM ANTIBODIES TO TYPE I COLLAGEN IN PERIPHERAL ARTHROPATHY ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE
Authors: D. Abdulganieva, D. Mukhametova, O. Zinkevich, N. Saphina, M. Korovina, A. Odincova
Journal: Annals of the Rheumatic Diseases (2022)

Background Immunological disorders play an important role in the pathogenesis of inflammatory bowel disease (IBD). Type I collagen (COL1) is the main component of the intercellular matrix of connective tissue. It can be assumed that the immune disorders leading to the production of autoantibodies to collagen play a role in the pathogenesis of arthropathy associated with IBD. Objectives to study the level of IgM and IgG to type I collagen (COL1) in peripheral arthropathy associated with IBD. Methods We prospectively included 91 patients with IBD [61 ulcerative colitis (UC), 30 Crohn’s disease (CD)] and 30 healthy controls. 82 patients with IBD were in disease attack and 9 in the remission Mean age in IBD was 36 [28; 47] years and in control group – 35 [25; 48]. Joint involvement (arthralgia, arthritis) was observed in 33 patients (36%). Affected joints were the knees 17 (51%), shoulders 6 (18%), feet 6 (18%), hands 5 (15%), elbows 4 (12%), ankles 3 (9%), wrists 2 (6%). Levels of serum IgM and IgG to COL1 were assessed by enzyme immunoassay. Results Levels of IgM to COL1 in active IBD (0,18 [0,10; 0,2] mkg/ml; р&lt;0,01) and in remission (0,15 [0,11; 0,20] mkg/ml; р&lt;0,05) were increased compared with healthy (0,09 [0,07; 0,12] mkg/ml). There were no differences between stage of disease (remission and exacerbation), IBD severity (p&gt;0,05). IgM antibodies to COL1 in patients with peripheral arthropathy (0,174 [0,12; 0,28] mkg/ml) were significantly higher than in patients without joint involvement (0,12 [0,08; 0,19] mkg/ml; р&lt;0,01). The levels of IgG to COL1 in active IBD (14,4 [10,22; 33,34] mkg/ml; р&lt;0,05) and in remission (28,82 [16,36; 78,9] mkg/ml; р&lt;0,005) were higher than in the control group 11,36 [6,93; 19,83] mkg/ml. We didn’t find any differences in IgG levels depending on the severity of disease. IgG levels to COL1 in patients with peripheral arthropathy (16,18 [9,46; 26,21] mkg/ml) were higher, than without them (12,78 [8,81; 28,31] mkg/ml), also not significant. Conclusion In active IBD the level of serum antibodies of class IgM and IgG to COL1 increased compared with healthy. The maximum increase was found in the patients with peripheral arthropathy, which can be explained by the high content of this collagen in the structural components of the joints and by joint inflammation in patients with IBD. Disclosure of Interests None declared.
AB1408 WELL-BEING AND MENTAL HEALTH OF RHEUMATOLOGY AND FAMILY MEDICINE RESIDENTS
Authors: M. Ketata, S. Miladi, A. Fazaa, H. Boussaa, L. Souabni, K. Ouenniche, S. Kassab, S. Chekili, K. Ben Abdelghani, A. Laatar
Journal: Annals of the Rheumatic Diseases (2022)

Background Burnouts and poor well-being among medical residents are becoming a global concern for health institutions. Its negative consequences are far-reaching, affecting patients, coworkers, family members, and healthcare organizations as well as the burned-out resident. Objectives The aim of the study was to measure the extent of burnout among rheumatology and family medicineresidents’and to elucidate wellness status as well as barriers to wellness. Methods An online questionnaire was issued to rheumatology and family medicine residents. We collected sociodemographic data (Age group, gender, marital status, children, smoking and alcohol status, Sport and other activities, Specialty, Weekly working Hours,Vacation) and mental health measurements. Participants were also requested to fill the 14-item Mental Health Continuum Short Form (MHC-SF) and the 5-item WHO-5 well-being form. Multivariable logistic regression analysis was used to explain the relationship between well-being and the work circumstances. Results A total of 64 residents with a 0,28 sex-ratio completed the online questionnaire. Sixty-nine percent (69%) of responders were in the [25-29] age group. Sixty three percent (63%) of responders were single and 14,1% had children. Most residents were not smokers (76,6%) nor alcohol users(68,8%). Eighty seven percent of responders were a family medicine resident. Thirty four percent (34%) of responders practiced sports 2 to 4 times a year and 25% exercised 2 to 4 times a week. The average working hours per week was 30 hours [10-70] with an average of 3,38 weeks’ vacation per year. Seventy eight percent (78%) of residents worked overnight shifts in hospitals with an average of 1,83 shift per month. Female sex (p=0,049), less physical activities (p=0,037) and long working hours (p=0,042) were associated with worst degree of quality of life (WHO5 Well-Being Index). Residents who practice art and had fewer overnight shifts showed a significantly flourishing mental health (p=0,032, p=0,014) according to the MHC-SF. Family medicine residents had more long working hours (p=0,039) and overnights shifts (p=0,047) than rheumatology residents. Conclusion Residents working more than 50 hours per week with more than 5 overnight shifts per month and those practicing fewer physical activities and art appear to be at high risk of developing languishing mental health according to the Who5 well-being index and the MHC-SF score. It is important to protect health care workers and to promote well-being to acquire a flourishing mental health. Disclosure of Interests None declared
AB1438 CARDIOVASCULAR RISK STRATIFICATION FOR TOFACITINIB PATIENTS IN A LARGE TEACHING HOSPITAL
Authors: A. Khatri, K. Tsoi, A. Rutherford
Journal: Annals of the Rheumatic Diseases (2022)

Background Tofacitinib is an oral JAK-Inhibitor often reserved for patients with treatment-resistant Rheumatoid Arthritis and Psoriatic Arthritis. Tofacitinib modulates cytokines crucial to the inflammatory response which characterises the above conditions, and inhibits certain pathways in the inflammatory response cascade. Rheumatoid and Psoriatic Arthritis are linked with an inherent increased risk for major cardiovascular events. Recent emerging data has evidenced increased cardiovascular risk associated with long-term use of tofacitinib. Objectives To identify all patients currently undergoing Tofacitinib treatment across all sites at King’s College Hospital NHS Foundation Trust.​ To risk-stratify all patients into three categories; low risk of developing major cardiovascular events, moderate risk of developing MACE (patients with modifiable risk factors​, eg. high cholesterol or a borderline blood pressure), and high risk of developing MACE (unmodifiable risk factors​). To switch patients at high risk onto another treatment or alternative JAK-inhibitor.​ Methods Patient data was obtained through electronic patient records including age, blood pressure reading, full lipid profile, smoking status, and comorbidities (hypertension, diabetes, chronic kidney disease, previous cardiovascular history and history of malignancy). A QRISK3 score was calculated. Modifiable risk factors with a lower QRISK3 score were categorised as moderate risk. Patients were considered at high risk if they had a previous cardiovascular event, or a QRISK3 score of more than 10%. Results A total of 40 patients were on tofacitinib; 64% with RA, 31% with PsA, and 5% for other reasons (interstitial lung disease and colitis). Of the rheumatoid arthritis cohort: 36% of patients were at high risk, 40% at moderate risk, and 24% low risk. Of the psoriatic arthritis cohort: 67% at high risk, 25% at moderate risk, 8% at low risk. Figure 1. Conclusion A significant number of patients were deemed at moderate and high risk. Patients with moderate risk were advised to undergo lifestyle changes, like exercise and diet modification and smoking cessation. Patients at high risk were discussed at the trust-wide Rheumatology local clinical governance meeting, and advised to switch onto an alternative treatment or alternative JAK-inhibitor. A repeat audit will be made in a few months’ time to assess the impact of lifestyle changes and alteration of drugs on cardiovascular risk. References [1]MHRA/CHM advice: Tofacitinib: new measures to minimise risk of major adverse cardiovascular events and malignancies (October 2021) Disclosure of Interests None declared
POS1192 INCIDENCE AND RISK FACTORS OF COVID‑19 IN PATIENTS WITH VASCULITIS: A DANISH NATIONWIDE COHORT STUDY
Authors: S. Kristensen, R. L. Cordtz, K. Duch, J. Lindhardsen, C. Torp-Pedersen, L. Dreyer
Journal: Annals of the Rheumatic Diseases (2022)

Background Patients with small vessel vasculitis (SVV) and large vessel vasculitis (LVV, including giant cell arteritis (GCA)) are considered at higher risk of infections compared to the general population, owing to their underlying condition and the use of immunosuppressive drugs. Thus, the risk of COVID-19 infection and related outcomes during the global pandemic is of immediate concern to rheumatologists worldwide. Objectives To estimate the incidence of COVID-19 hospitalisation in patients with vasculitis, and to evaluate the impact of glucocorticoid treatment on the outcome between March 2020 and February 2021. Methods With use of the Danish nationwide registers, a cohort of patients with LVV and SVV, respectively, and general population controls (GPCs) matched on age and gender was established. Hazard ratios (HR) for COVID-19 hospitalisation was estimated. National COVID-19 surveillance data was used to calculate the odds ratio (OR) of having had a positive SARS-CoV2 PCR test. Lastly, a nested case-control design and conditional logistic regression was used to estimate the impact of glucocorticoids on the risk of hospitalisation. Results Patients with SVV (n=1090) had an increased incidence of COVID-19 hospitalisation compared with GPCs (comorbidity-adjusted HR 2·73; 95% CI 1·64-4·55), whereas no increased risk was seen in patients with LVV. Patients with vasculitis had similar likelihoods of having had a positive PCR test as GPCs. Glucocorticoids did not increase the HR of hospitalisation among patients with LVV or SVV. Conclusion Patients with SVV were more likely to be admitted with COVID-19 than the GPCs. The impact of glucocorticoid treatment on the risk of hospitalisation needs further investigation. References [1]Cordtz R, Lindhardsen J, Soussi BG, et al. Incidence and severeness of COVID-19 hospitalization in patients with inflammatory rheumatic disease: a nationwide cohort study from Denmark. Rheumatology. Published online 2020. doi:10.1093/rheumatology/keaa897 [2]Rutherford MA, Scott J, Karabayas M, et al. Risk factors for severe outcomes in patients with systemic vasculitis &amp; COVID-19: a bi-national registry-based cohort study. Arthritis Rheumatol. Published online 2021. doi:10.1002/art.41728 [3]Tomelleri A, Sartorelli S, Campochiaro C, Baldissera EM, Dagna L. Impact of COVID-19 pandemic on patients with large-vessel vasculitis in Italy: A monocentric survey. Ann Rheum Dis. Published online 2020. doi:10.1136/annrheumdis-2020-217600 Disclosure of Interests Salome Kristensen: None declared, René Lindholm Cordtz: None declared, Kirsten Duch: None declared, Jesper Lindhardsen: None declared, Christian Torp-Pedersen Grant/research support from: Recieved grants from Bayer and Novo Nordisk outside the present work, Lene Dreyer Grant/research support from: Received research grant/research support from BMS, and speakers bureau from EliLilly and Galderma outside the present work.